The direct aims of the proposed investigation are elucidation of the mechanism for squalene biosynthesis from farnesyl pyrophosphate, development of specific inhibitors of this transformation, and definition of the alternative metabolism of farnesyl pyrophosphate in animals. The results of these studies are not only of fundamental significance but are potentially important to the treatment of cardiovascular diseases. The experimental approach to the first two goals involves the use of synthetic substrate analogues designed to interfere with the normal course of the reaction sequence, thereby revealing mechanistic details and/or inhibiting the enzyme involved. Elucidation of the alternate metabolic pathway for farnesyl pyrophosphate will be approached not only by the usual attempts to isolate metabolities of labeled farnesol, but also by the use of possible synthetic metabolites as substrates and diluting "pools".